Ex 3 L5: Topical and Transdermal Drug Delivery Flashcards
Physiology of the skin: Stratum corneum
Stratum corneum
Main barrier to permeation
Brick and mortar model
-Bricks: dead cells
-Mortar: lipid
Dead cells are not permeable
-Gets affected by hydration status
Permeation occurs by partitioning through the lipid material (mortar) between the dead cells (bricks)
Functions as a lipid barrier
State of hydration is directly related to the ease of permeation
Physiology of the skin: Living epidermis, dermis, hair follicles and sweat glands
Living epidermis (Viable epidermis)
-Living cells w/o capillaries. Cells get nutrition by diffusion from dermis
-Source of skin color and tanning
Dermis
-Contains capillaries
-Drug needs to reach these capillaries to achieve systemic action
-Contains pain, thermal, and tactile sensors
-Injury must reach dermis to produce scarring
-nerves - feel pain, bleed
hair follicles and sweat glands
-Secondary route of drug absorption that bypasses the stratum corneum
Functions of the skin
Containment
-Confine underlying tissues and restrain their movement
Microbial barrier
-pH of skin is 5, which inhibits the growth of bacteria
-Sebum contains bacteriostatic and fungistatic fatty acids (propanoic, butanoic, hexanoic, and heptanoic acids)
Chemical barrier
-Permeability resistance of stratum corneum is several orders of magnitude greater than other barrier membranes of the body
Radiation barrier
-Exposure to UV stimulates synthesis of melanin, which absorbs UV rays
Electrical barrier
-Offers high impedance of the flow of an electrical current
-Need to treat the skin with salt solutions and overcome the impedance to measure body potentials (electroencephalograms or electrocardiograms). Use granular salt suspensions, creams, pastes containing electrolytes
Thermal barrier and body temperature regulation
-Maintains 98.6 degrees F (37C) by dilating/contracting blood vessels or sweating
Topical/Transdermal drug delivery
Topical
-Local effects on barrier function
-surface effects
-stratum corneum effects
-Drug action on the skin’s glands
-Effects in deep tissues
Transdermal
-Systemic drug delivery
Topical drug delivery
Local effects on barrier function
Surface effects
-Zinc oxide paste for diaper rash
-Sun blocks and sun screens
-Lip balms for chapped lips
-Calamine lotion for poison ivy and poison oak
-Antibiotics
-Deodorants
-Medicated soaps
Stratum corneum effects
-Emoliency: softening horny tissue
-Keratolysis: Chemical digestion and removal of horny tissue
Topical Drug Delivery
Drug action on the skin’s glands
-Antiperspirants
-Aluminum chloride (irritate & close the orifice of eccrine glands to impede sweat flow)
-Acne
-Soap, alcoholic solutions, antibiotics,
-Retinoids (reset the processes of epidermal proliferation and differentiation -> prevents the formation of lesions)
-Hair removers (depilatories)
Effects in deep tissues
-Topical corticosteroids
-Non-steroidal anti-inflammatory drugs: diclofenac
Local anesthetics: benzocaine
Lighten excessively pigmented skin: hydroquinone
Skin cancer: 5-fluorouracil
Topical drug delivery platforms
Ointments
more hydrophobic
-Hydrocarbon bases
-pertrolatum
-Polyethylene dissolved in mineral oil (Plastibase)
-Silicone bases - contains polydimethylsiloxane oil
-Absorption bases
-Ointment containing W/O emulsifiers (i.e., W/O emulsion containing aqueous solution of a drug)
-Water soluble bases
-Polyethylene glycol ointment
more hydrophilic
Topical drug delivery platforms cont.
Pastes
-Ointments into which a high concentration of insoluble particulate solids (starch, calcium carbonate, talc) are added
Creams
-O/W or W/O emulsion
Gels
-Liquid phase trapped in matrix of a natural or synthetic polymer (tragacanth, pectin, carrageenan, methylcellulose, carboxymethylcellulose, carbapol)
-Eg topical scalp gels (not too greasy)
Rigid foams
-Air or other gas emulsified in a liquid phase (like whipped cream)
-Liquid phase may contain a drug
-Aerosol shaving creams, medicated quick-breaking antiseptic foams
Transdermal drug delivery
-Some drugs can penetrate the skin and enter systemic circulation
-Of particular interest for drugs that have a short systemic half-life, undergo extensive first-pass metabolism, thus, requiring frequent dosing
have to enter dermis
Transdermal drug delivery cont
Generally impenetrable
-Principle resistance is stratum corneum
Permeability correlates with drug’s MW and Ko/w
-LogP ~= -2.7 +0.71logKo/w -0.0061M
-P: permeability coefficient
M: Molecular weight (<1000 Da)
Ko/w: Oil/water partition coefficient
Useful for drugs with:
-High skin permeability
-Low dose requirement
Drugs in transdermal patches
Nicotine
Clonidine
Nitroglycerin
-Membrane modulated
-Adhesive dispersion
-Matrix dispersion
Estradiol
Scopolamine
-Membrane modulated
Fentanyl
Transdermal nitroglycerin
Nitroglycerin (227.09 Da)
Half-life: 3 min
Slightly soluble in water, soluble in common organic solvents
Indication: Prevention of angina pectoris (Chest pain) due to coronary artery disease; not for immediate relief of acute attacks
Transdermal Rivastigmine
Exelon Patch (Novartis)
Approved by FDA: 2007
Indicated for memory problems (dementia0 associated with Alzheimer’s or Parkinson’s disease
4.6 mg/24h, 13.3mg/24h
-A total daily dose of <6mg of oral rivastigmine -> 4.6mg/24h
-A total daily dose of 6-12 mg of oral rivastigmine -> 9.5 mg/24h
Transdermal rivastigmine
Rivastigmine
MW: 250.34 Da
Sparingly soluble in water, very soluble in ethanol, acetonitrile, n-octanol, ethyl acetate
LogP: 2.3; water solubility: 2.04 mg/mL
Transdermal contraceptive
Ortho Evra (Janssen) - discontinued in 2014
Xualne (Mylan)
150 mcg/day norelgestromin and 35 mcg/day ethinyl estradiol
Matrix-type transdermal system
-Backing layer: Polymer layer for structural support
-Middle layer: Adhesive + Matrix + active ingredients
-Third layer: release liner
Once a week for three weeks
Upper outer arm, abdomen, buttock or back
Drug diffusion through skin
Protein-rich cells (bricks) separated by thin layer intercellular lipids (mortar)
1. Across the cellular-intercellular regions
2. Across the lipid intercellular spaces
3. Across thin lipid layers sandwiched between the flattened protein cells
Factors affecting permeability
Hydration
-The more hydrated, the greater drug permeability
-Water associated with polar head groups of lipid bilayer loosens the lipid packing and make the bilayer more fluid
Penetration enhancement
Iontophoresis
-Uses low voltage electrical current to drive charged drugs through the skin
Electroporation
-Uses high voltage (short) to create transient pores in the skin
-Early stage, but very good
Ultrasound
-Uses low frequency ultrasonic energy to disrupt the stratum corneum
prodrugs
-Make lipophilic
(chemical) Penetration enhancers
-Alcohol, dimethyl sulfoxide (DMSO), surfactants, acetone, ethyl acetate
Enhancers
Ionic surfactants
-Disorder the lipid layer of stratum corneum to swell and/or leach out some of the structural components, thus reducing the diffusional resistance
Ascorbate, dithiothreitol
-Reducing agents. Disrupt disulfide bonds of proteins in keratinized cells
Azone
-Nonpolar, oily liquid. Fluidize intracellular lipid lamella region of stratum corneum
Dimethyl sulfoxide (DMSO)
-Dipolar solvent. Enter aqueous region of stratum corneum, interact with the lipid polar heads to expand hydrophilic region between polar heads
Microneedles
Dissolving microneedles: type of polymeric MN that can degrade or dissolve postinsertion into the skin, leading to the delivery of the encapsulated drug at the site of application
Hydrogel forming microneedles.
have cross-linked hydrogel structure that can collect interstitial fluid upon skin application -> in-situ hydrogel
Separable microneedles
-Rapidly dissolvable backing layers; with weaker connections between the backing layers and the MN tips; or based on a hydrogel backing layer
Hollow microneedles
-Each needle incorporates a hollow cavity within and a bore on the needle tips, to which small volumes of drug solutions can be injected
Patches
Common application sites
-Chest (upper)
-Back (upper and lower)
-Upper arm (on the part facing out)
-Flanks (sides of the body, abdomen level): Except for exelon
Frequency
-Daily (e.g. nicotine, rivastigmine)
-Twice daily (diclofenac)
-Twice weekly
-Weekly (e.g. Buprenorphine, clonidine, estradiol)
-Every 72 hrs (e.g. Fentanyl)
Common errors in transdermal patch admin
Preparation
-Removal of the patch from the packaging
-Removal of the protective foil
-Alternation of the patch
Removal
Application
Monitoring
-Influence of heat
-Patch displacement
Storage and disposal
Some patients do not realize…
Patch must be applied directly to the skin (they should not tape a patch on top of the other)
They must remove the protective liner
They need to use one patch at a time (6 fentanyl patches)
Where to place (recommended locations; rotate the area of application to avoid skin irriation)
When to change
Transparent patches
TTS: Therapeutic System vs Tues, Thurs, & Saturday
Pediatric patch issue: Some patches should not be cut
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